Method of treating middle ear infections

ABSTRACT

Aqueous suspension formulations containing dexamethasone and ciprofloxacin are disclosed for the treatment of middle ear infections in human patients having an open tympanic membrane.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation (CON) of co-pending U.S. applicationSer. No. 12/357,697 filed Feb. 13, 2009; which is a Continuation ofapplication Ser. No. 12/119,185 filed May 12, 2008 now abandoned; whichis a Continuation of application Ser. No. 10/946,792 filed Sep. 22, 2004now abandoned; which is a Divisional of application Ser. No. 10/243,341filed Sep. 13, 2002 now abandoned, priority of which is claimed under 35U.S.C. §120, the contents of which are incorporated herein2 byreference. This application also claims priority under 35 U.S.C. §119 toU.S. Provisional Application Ser. No. 60/323,951, filed Sep. 21, 2001,the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention relates to the use of formulations of ciprofloxacin anddexamethasone to treat otic infections. Specifically, the inventionrelates to the topical use of such a fixed combination to treat middleear infections in humans.

External ear infections, known as acute otitis externa (“AOE”), arecurrently treated with oral antibiotics, topical single-entityantibiotics, or topical antibiotic/steroid combination products. Anexample of an oral antibiotic product used to treat AOE is AUGMENTIN®(amoxicillin and clavulanic acid). An example of a single-entityantibiotic product approved for topical use in treating AOE is FLOXIN®(ofloxacin). Examples of combination products approved for this useinclude CORTISPORIN® (hydrocortisone, neomycin sulfate, and polymyxin bsulfate) and CIPRO®HC (ciprofloxacin and hydrocortisone). A productcalled SOFRADEX (gramicidin, framycetin and hydrocortisone) is availablein some European countries and in Australia. External ear infectionstypically involve bacteria of the following types: Pseudomonasaeruginosa, Staphylococcus aureus. Staphylococcus sp. and Coryneforms.

In contrast, middle ear infections known as otitis media (“OM”)typically involve bacteria of the following types: S. pneumonia, H.influenzae and M. catarrhalis. Patients with chronic or severe middleear infections may have their ear drums (tympanic membranes)intentionally punctured and drainage tubes, often referred to as atympanostomy tubes, implanted. In other cases, particularly in patientswith severe OM, the tympanic membrane may rupture. Whether surgicallypunctured or accidentally ruptured, open tympanic membranes allow thebacteria characteristic of AOE and OM to mix.

Patients with OM are currently treated with oral antibiotics such asAUGMENTIN®. When drainage through an open tympanic membrane into theouter ear persists, either an oral antibiotic (e.g., AUGMENTIN®) or atopical antibiotic (e.g., FLOXIN®) is often prescribed. Additionally,topical antibiotic/steroid combination products approved for AOE havebeen used “off-label” in some cases to treat OM in patients with an opentympanic membrane, including CORTISPORIN®, CIPRO®HC, and TOBRADEX®(tobramycin and dexamethasone). To date, however, no topicalantibiotic/steroid combination product has been approved by the Food andDrug Administration in the U.S. for the treatment of OM in patients withan open tympanic membrane.

Fixed combination products containing ciprofloxacin and dexamethasoneare known. Although no such product is currently approved in the U.S.,this combination is commercially available for ophthalmic use in certaincountries in South America as Biomotil-D (Allergan Frumtost) and Cilodex(Alcon Laboratories). Although the use of ciprofloxacin/dexamethasonecombinations for the treatment of ocular and/or otic infections has beendisclosed in the scientific and patent literature (see, for example,Spanish Patent Application No. 2,065,846 A1 (Feb. 16, 1995), WO 90/01933and U.S. Pat. No. 6,284,804), there has been no disclosure of the use ofsuch a combination specifically for treating OM in patients with opentympanic membranes.

SUMMARY OF THE INVENTION

The present invention provides a method of topically treating OM inhuman patients who have open tympanic membranes. The method involves thetopical application of a fixed combination of ciprofloxacin anddexamethasone as an aqueous suspension product. Although the dosingregimen may vary depending on the age and weight of the patient, as wellas the severity of the infection, in most cases, the combination productwould be applied twice a day. Each application would involve topicallyadministering three or four drops into the ear canal, preferably pumpingthe tragus to force product through the opening in the tympanic membraneand to the site of the infection/inflammation in the middle ear.

Among other factors, the present invention is based on the finding thatan aqueous combination of ciprofloxacin and dexamethasone was notstatistically more effective than ciprofloxacin alone in the treatmentof AOE, but was surprisingly statistically more effective thatciprofloxacin alone in the treatment of OM in patients with an opentympanic membrane. The fact that a contribution of elements forciprofloxacin and dexamethasone could be demonstrated for only OM andnot AOE was not predictable, nor was the fact that such a contributionof elements would be shown in OM.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the average number of days to time of cessation of ear painin a human clinical study comparing a ciprofloxacin/dexamethasonecombination product to a ciprofloxacin single-entity product.

FIG. 2 shows the average number of days to cessation of otorrhea in ahuman clinical study comparing a ciprofloxacin/dexamethasone combinationproduct to a ciprofloxacin single-entity product.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, all ingredient amounts presented as apercentage are in units of weight %.

The methods of the present invention involve diagnosing a human patientas having OM and an open tympanic membrane. “Open tympanic membrane”means that the membrane has been intentionally punctured, with orwithout tympanostomy tube implantation, or has accidentally ruptured.Once diagnosed with OM and an open tympanic membrane, the method of thepresent invention involves topically administering to the ear canal ofthe patient's affected ear an aqueous suspension formulation of a fixedcombination of ciprofloxacin and dexamethasone. OM includes, but is notlimited to, acute otitis media and chronic supprative otitis media.

Dexamethasone can be present in any ophthalmically or oticallyacceptable form having poor water solubility such that the resultingformulation is a suspension formulation. Suitable forms of dexamethasoneinclude dexamethasone alcohol (alcohol form of dexamethasone),dexamethasone acetate and dexamethasone phosphate. Dexamethasone alcoholis the preferred form of dexamethasone. The average particle size (meanvolume basis) of the dexamethasone ingredient should be less than 10 μmto avoid irritation or discomfort. The average particle size ispreferably less than 6 μm and most preferably less than 3 μm.Dexamethasone particles can be sized using known techniques, such asball-milling, microfluidization and sonication. The ciprofloxaciningredient can be any otically acceptable form such that theciprofloxacin ingredient is in solution in the final formulation. Apreferred form of ciprofloxacin is ciprofloxacin hydrochloride,monohydrate.

The dexamethasone ingredient will comprise about 0.01-0.5% and theciprofloxacin ingredient will comprise about 0.1-0.4% of the aqueoussuspension formulations administered according to the present invention.The preferred amounts of dexamethasone and ciprofloxacin in theformulations used in the present invention are 0.1% and 0.3%,respectively.

In addition to the active agents, the suspension formulations used inthe present invention contain a tonicity agent. The tonicity agent maybe ionic (e.g., NaCl) or nonionic (e.g., mannitol). The tonicity agentis preferably NaCl. The amount of NaCl will depend on the desiredtonicity for the final formulation, but will generally range from0.1-0.9%. The suspension formulations of the present inventionpreferably contain an amount of tonicity agent sufficient to cause theformulations to have an osmolality of about 250-350 mOsm.

The suspension formulations also contain a nonionic polymer as asuspending agent. Many otically acceptable nonionic polymers are known.These polymers include hydroxyethyl cellulose; hydroxypropylmethylcellulose; methyl cellulose; carboxymethyl cellulose; polyvinylpyrrolidone and polyvinyl alcohol. The preferred nonionic polymer ishydroxyethyl cellulose. The nonionic polymer will be present in theformulations of the present invention in an amount of about 0.1-0.5%. Inthe case of hydroxyethyl cellulose, the preferred concentration ofnonionic polymer is 0.2%.

The formulations of the present invention also contain a nonionicsurfactant in an amount from about 0.01-0.2%. Many otically acceptablenonionic surfactants are known. Suitable nonionic surfactants includetyloxapol; polyoxyethylene sorbitan esters, such as polysorbate 20,polysorbate 60, and polysorbate 80; polyethoxylated castor oils, such asCremaphor EL; polyethoxylated hydrogenated castor oils, such as HCO-40;and poloxamers. The preferred surfactant is tyloxapol.

If desired, the formulations may contain a quaternary ammonium halide asa preservative. Suitable quaternary ammonium halides includepolyquaternium-1 and benzalkonium halides. Preferred benzalkoniumhalides are benzalkonium chloride (“BAC”) and benzalkonium bromide. Ingeneral, the amount of the preservative ingredient will range from about0.005-0.3%. In the preferred case where the preservative is BAC, it ispreferably present at a concentration of 0.01%.

If desired, a chelating agent may also be present in the suspensionformulations used in the methods of the present invention. Suitablechelating agents include edetate disodium (“EDTA”); edetate trisodium;edetate tetrasodium; and diethyleneamine pentaacetate. Most preferred isEDTA. The chelating agent, if any, will typically be present in anamount from about 0.001-0.1%. In the case of EDTA, the chelating agentis preferably present at a concentration of 0.01%.

In the case of preserved or multi-dose formulations, the suspensionformulations of the present invention may contain boric acid in anamount from 0.1-1.5%.

The formulations administered according to the present invention have apH from 3-6, preferably 4.5. pH can be adjusted with NaOH/HCl. Thepreferred buffering system for these formulations is a combination ofsodium acetate and acetic acid. The concentration of sodium acetate willgenerally range from 0.015-0.06%, and will preferably be about 0.03%.The concentration of acetic acid will generally range from 0.02-0.08,and will preferably be about 0.04%.

Though physicians may prescribe other dosing regimens depending on anumber of factors including the severity of the OM, the age and weightof the patient, etc., the ciprofloxacin/dexamethasone combinationproducts administered according to the present invention will generallybe administered twice a day. Each administration will typically involveplacing 3-4 drops (with a typical drop volume of 30-35 μL) of thesuspension product in the affected ear. Preferably, the patient willpump the tragus of the affected ear to force the administered productthrough the opening in the tympanic membrane and to the site of theinfection/inflammation in the middle ear.

In one embodiment, the present invention relates to aciprofloxacin/dexamethasone aqueous suspension composition that ispackaged with directions for use that indicate the composition may beused to treat otitis media in patients with an open tympanic membrane.As used herein, “directions for use” includes information contained inproduct labeling, package inserts and cartons or other packagingmaterials that accompany the ciprofloxacin/dexamethasone aqueoussuspension composition of the present invention.

The following examples are intended to illustrate, but not limit, thepresent invention.

Example 1 Representative Formulations

A B C D E Ingredients % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) Cipro-0.35* 0.35 0.35 0.35 0.35 floxacin HCl, Monohydrate Dexa- 0.1 0.1 0.10.1 0.1 methasone Alcohol Hydroxy- 0.2 0.2 0.2 0.2 0.2 ethyl CelluloseBenzal- 0.01 0.01 0.01 0.01 0.01 konium Chloride Sodium 0.03 0.03 0.030.03 0.03 Acetate (Trihydrate) Acetic Acid 0.04 0.04 0.04 0.04 0.04Sodium 0.25 0.25 0.80 0.53 — Chloride Edetate 0.01 0.01 0.01 0.01 0.01Disodium Tyloxapol 0.05 0.05 0.05 0.05 0.05 Glycerin 1.5 — — — 2.35Boric Acid — — — 0.6 — NaOH/HCl q.s. pH q.s. pH q.s. pH q.s. pH q.s. pH4.5 ± 0.2 4.5 ± 0.2 4.5 ± 0.2 4.5 ± 0.2 4.5 ± 0.2 Purified q.s. 100 q.s.100 q.s.100 q.s. 100 q.s. 100 Water Osmolality 272 99 274 286 290 (mOsm)*equivalent to 0.3% ciprofloxacin baseFormulations A-E were made using the following method:

-   (1) For a formulation batch size of 500 ml, form a slurry by    combining 75 g of 3 mm zirconium beads, 12 g of tyloxapol 1.0% stock    solution and 0.5 g dexamethasone alcohol in a 30 ml polypropylene    milling bottle (approx. 48% of the final batch requirement of    tyloxapol is used);-   (2) steam sterilize (autoclave) the slurry, including beads;-   (3) aseptically ball mill the sterilized slurry for 18 hrs at 50 to    55 rpm;-   (4) prepare an aqueous solution containing the remaining requirement    of tyloxapol and the required amounts of all remaining ingredients    (e.g., in the case of Formulation D, the remaining ingredients are    ciprofloxacin hydrochloride monohydrate, benzalkonium chloride,    sodium acetate, acetic acid, sodium chloride, hydroxyethylcellulose,    boric acid, edetate disodium, and purified water;-   (5) steam sterilize (autoclave) the aqueous solution prepared in    step (4);-   (6) combine the sterile slurry obtained in step 3 to the sterile    solution obtained in step 5 by aseptically pouring the slurry    through a sterile sieve (to remove the beads) into the solution    obtained in step 5;-   (7) adjust the formulation weight to 80-90% of batch weight using    sterile-filtered purified water;-   (8) check the final pH and adjust to pH 4.5±0.2 by sterile-filtered    sodium hydroxide or hydrochloric acid, if needed; and-   (9) bring the formulation to 100% of batch weight using    sterile-filtered purified water.

An alternative method of preparing Formulations A-E, especially when thedexamethasone raw material is supplied or available already meeting thedesired particle size specifications, is as follows:

-   (1) dry heat sterilize the dexamethasone raw material (recommended    specification: between 7-11 hrs. at 130-140° C. (internal powder    temperature);-   (2) prepare a tyloxapol solution containing the batch requirement of    tyloxapol in purified water;-   (3) sterilize the tyloxapol solution by passing it through a 0.2 μm    filter;-   (4) aseptically combine the sterilized dexamethasone with the    sterilized tyloxapol solution to form a sterile slurry and stir    until homogenous;-   (5) prepare an aqueous solution containing the required amounts of    the remaining ingredients (e.g., in the case of Formulation D, the    remaining ingredients are ciprofloxacin hydrochloride, monohydrate    benzalkonium chloride, sodium acetate, acetic acid, sodium chloride,    hydroxyethylcellulose, boric acid, edetate disodium and purified    water;-   (6) steam sterilize (autoclave) the aqueous solution prepared in    step (5);-   (7) aseptically combine the sterile slurry prepared in step (4) with    the sterilized solution prepared in step (6);-   (8) adjust the formulation weight to 80-90% of batch weight using    sterile-filtered, purified water.-   (9) check the final pH and adjust to pH 4.5±0.2 by sterile-filtered    sodium hydroxide or hydrochloric acid, if needed; and-   (10) bring the formulation to 100% of batch weight using    sterile-filtered purified water.

Example 2 AOE Clinical Study in Human Patients

A clinical study with a primary objective of demonstrating superiorityof a ciprofloxacin/dexamethasone combination product (ciprofloxacin0.3%, dexamethasone 0.1%; Formulation D above) (“CIPRODEX”) relative tothe marketed CILOXAN® single-agent (ciprofloxacin 0.3%; AlconLaboratories, Inc.) product for time to cessation of ear pain inpatients with moderate to severe acute otitis externa (AOE) wasconducted. A summary of the study details for this AOE study is providedbelow.

Summary of AOE Study CIPRODEX (Ciprofloxacin 0.3%) Suspension vs.CILOXAN (Ciprofloxacin 0.3%) Solution vs. CORTISPORIN Suspension(Neomycin 0.35%, Polymyxin B 10,000 IU/mL, Hydrocortisone 1.0%) forTopical Treatment of patients with moderate to severe Acute OtitisExterna (AOE). Study Design: Phase III multicenter, randomized,single-blind, active controlled, parallel group study. Study Primaryobjectives of the study were to demonstrate: Objectives: Superiority ofCIPRODEX combination relative to CILOXAN single agent for time tocessation of ear pain. Therapeutic non-inferiority of CIPRODEXcombination relative to CILOXAN single agent based on clinical responseat the test of cure (TOC) visit (Day 18). Therapeutic non-inferiority ofCIPRODEX combination relative to CORTISPORIN combination for clinicalresponse at the TOC visit. Therapeutic non-inferiority of CILOXAN singleagent relative to CORTISPORIN combination for clinical response at theTOC visit. Patient A total of 909 patients enrolled into the study at 48investigative sites in Population: the United States between April 1998and May 2000. Inclusion Clinical diagnosis of moderate or severe AOE, atleast one year of age, Criteria: gave informed consent, and agreed tofollow study procedures. Posology: Eligible patients were treated for 7days with three drops BID CIPRODEX (n = 305), three drops BID CILOXAN (n= 305), or four drops TID CORTISPORIN (n = 299). Study Visits: Day 1,Day 3, Day 8 (End of Therapy, EOT), and Day 18 (TOC). Clinical Patientassessment of pain and tenderness using a daily diary. Evaluation:Physician evaluation of signs and symptoms of AOE, includinginflammation, tenderness, edema, and otic discharge by visit.Microbiology: Microbiology outcomes were based on presumed or confirmedbacterial eradication. Efficacy Cessation of ear pain was defined as thefirst day where the patient dairy Criteria: pain score was zero, with noanalgesics used in the prior 24 hours, and the ear pain score remainedzero for all subsequent entries. Physician's assessment of clinicalresponse of the patient at TOC on a 4-point scale (0 = cured, 1 =improved, 2 = no change, 3 = worse). Safety Based on the frequency andincidence of adverse events reported. Evaluation: Overall Time tocessation of pain is not different between CIPRODEX and Conclusions:CILOXAN treatments (i.e., no contribution of elements). CIPRODEX isnon-inferior to CILOXAN for clinical cures and microbiologicaleradication. CIPRODEX produces more clinical cures than CORTISPORIN andis non-inferior for microbiological eradication. CILOXAN is superior toCORTISPORIN for clinical response in culture positive patients, andnon-inferior for microbial eradication. CIPRODEX and CILOXAN are safeand well tolerated in pediatric and adult patients with AOE.

Time to no pain was evaluated for CIPRODEX and CILOXAN, with the resultsshown in Table 1 and FIG. 1. These results show the average number ofdays to cessation of ear pain for the “modified intent-to-treat”(“MITT”) population of the study. MITT is a term of art in the clinicalsciences. For this study, the MITT population is defined as thepopulation that received study drug, met inclusion criteria and wasculture positive for bacteria on Day 1. The MITT population for thisstudy comprised 267 patients for CIPRODEX and 261 patients for CILOXAN.

TABLE 1 MITT: Time to No Pain (in days) Treatment Mean Median CIPRODEX6.8* 5.0 CILOXAN 6.3 5.0 *p-value = 0.29 (Log-Rank Test; Kaplan-MeierLife Table Survival Estimates)

Data obtained in this AOE study demonstrate that time to cessation ofear pain was not different between CIPRODEX and CILOXAN, and therefore,no contribution of elements was shown for CIPRODEX. These results show aslight advantage for CILOXAN (6.8 days) over CIPRODEX (6.3 days) inaverage time to no otorrhea, but the differences were not statisticallysignificant (p-value=0.29).

Example 3 OM with Open Tympanic Membrane Clinical Study in HumanPatients

A clinical study with a primary objective of showing therapeuticsuperiority of CIPRODEX (Formulation D above) relative to CILOXAN forcessation of otorrhea (ear discharge) in tympanostomy tube patients withAcute Otitis Media (AOM) was conducted. A summary of the study detailsfor this OM study is provided below.

Summary of AOM Study Safety and Efficacy of Topical CIPRODEX(Ciprofloxacin 0.3%, Dexamethasone 0.1%) Suspension Compared to CILOXAN(Ciprofloxacin 0.3%) Solution in the Treatment of Acute Otitis Mediawith Tympanostomy Tubes (AOMT) Study Design: Phase II multicenter,randomized, evaluator-blind, active controlled, parallel group study.Study The study objectives were to: Objectives: Demonstrate therapeuticsuperiority of CIPRODEX combination relative to CILOXAN single agent forcessation of otorrhea, and to Evaluate the efficacy and safety oftopical CIPRODEX Suspension in AOMT patients Patient A total of 201patients enrolled into the study at 21 investigative sites inPopulation: the United States between March 2000 and January 2001.Inclusion Pediatric patients (6 months to 12 years) with a patenttympanostomy Criteria: tube and clinically diagnosed with acute otitismedia with otorrhea that is visible by the parent/guardian of 3 weeks orless duration. Posology: Eligible patients were treated for 7 days withBID CIPRODEX (n = 103) or 7 days with BID CILOXAN (n = 98). StudyVisits: Day 1, Day 3, Day 8 (End of Therapy, EOT), and Day 14 (Test ofCure, TOC). Clinical Twice daily patient assessment of cessation ofotorrhea using a daily Evaluation: diary. Physician evaluation of signsand symptoms of AOMT, including presence of otorrhea, characteristics ofotorrhea, presence of granulation tissue, tube patency, and overallclinical response by visit. Microbiology: Microbiology outcomes werebased on presumed or confirmed bacterial eradication. Efficacy Cessationof otorrhea was defined as ending on the first day on which Criteria:the otorrhea is absent and remains absent for all subsequent diaryentries. Physician's assessment of clinical response of the patient atTOC on a 4-point scale (0 = resolved, 1 = improved, 2 = no change, 3 =worse). Safety Based on the frequency and incidence of adverse eventsreported. Evaluation: Overall CIPRODEX has a statistically significantlyshorter Time to Conclusions: Cessation of Otorrhea when compared toCILOXAN (using Log- Rank test of equality over strata). CIPRODEX isstatistically significantly more effective than CILOXAN for Physician'sClinical Impression at the Day 3 Visit, but not at the Day 8 or Day 14Visits (using Cochran-Mantel-Haenszel Rank Scores Test). Nostatistically significant differences were detected between CIPRODEX andCILOXAN for Microbiological Eradication Rates at the Test of Cure Visit(using Fisher's Exact Test). CIPRODEX and CILOXAN are safe and welltolerated in pediatric with AOMT.

The results of this study for the MITT population are presented in Table2 and FIG. 2. For this study, the MITT population is defined as thepopulation that received study drug, met inclusion criteria,participated in at least one on-therapy visit, and was culture positivefor bacteria on Day 1. The MITT population for this study comprised 87patients for CIPRODEX and 80 patients for CILOXAN.

TABLE 2 MITT: Time to No Otorrhea (in days) Treatment Mean Median Std. NMin. Max. CIPRODEX 4.22* 4 2.04 87 2 10 CILOXAN 5.31 5 1.94 80 2 10*p-value = 0.0040 (Log-Rank test of equality over strata)

The results of this OM demonstrate a clinically and statisticallysignificant difference in the time to cessation of otorrhea forCIPRODEX-treated patients (4.03 days) compared to CILOXAN-treatedpatients (5.06 days), approximately a 20% reduction in time to nootorrhea. In this study, contribution of elements for CIPRODEX wasshown.

Example 4 CIPRODEX vs. FLOXIN Study

A clinical study comparing CIPRODEX (Formulation D above) to FLOXIN inthe treatment of tympanostomy tube patients with Acute Otitis Media(AOM) was conducted. A summary of the study details for this OM study isprovided below.

Summary of CIPRODEX vs. FLOXIN Study

Safety and Efficacy of Topical CIPRODEX Otic (Ciprofloxacin0.3%/Dexamethason 0.1%) Suspension Compared to FLOXIN Otic (Ofloxacin0.3%) Solution in the Treatment of Acute Otitis Media with TympanostomyTubes (AOMT)

Study Design:

Phase III, randomized, evaluator-masked, active-controlled,parallel-group study.

Objectives:

-   -   To demonstrate the non-inferiority of CIPRODEX Otic Suspension        relative to FLOXIN Otic Solution in clinical and microbiological        response at the test of cure (TOC) visit; and    -   To evaluate the efficacy and safety of CIPRODEX Otic Suspension        for the treatment of patients with acute otitis media and        otorrhea with tympanostomy tubes (AOMT).        Patient Population:

Approximately 500 pediatric patients with AOMT and post-tympanostomytube otorrhea (250/arm) were planned. A total of 599 patients wereenrolled.

Diagnosis and Main Criteria for Inclusion:

Pediatric patients, from 6 months to 12 years of age, with a patenttympanostomy tube, clinically diagnosed with acute otitis media andotorrhea of 3 weeks or less duration, visible by the parent/guardian,were enrolled.

Test Product, Dose and Mode of Administration, Batch Number(s):

CIPRODEX Otic (ciprofloxacin 0.3%/dexamethasone 0.1%) Suspension;topical otic administration of 4 drops into the infected ear(s) twicedaily (BID) for 7 days.

Duration of Treatment:

Patients were required to undergo treatment for either seven (7) days ifrandomized to receive CIPRODEX or ten (10) days if randomized to receiveFLOXIN.

Reference Therapy, Dose and Mode of Administration, Batch Number(s):

FLOXIN Otic (ofloxacin 0.3%) Solution; topical otic administration of 5drops into the infected ear(s) twice daily (BID) for 10 days.

Criteria for Evaluation:

Subsequent to the demonstration of non-inferiority, superiority analyseswere conducted. Analyses for the determination of superiority were basedon the data set of patients who received treatment, had a positivepre-therapy culture and met the inclusion/exclusion criteria forenrollment (modified intent-to-treat, MITT). Analyses were alsoconducted for the intent-to-treat (ITT), per protocol (PP) and modifiedper protocol (MPP) data sets.

Efficacy:

The two primary variables were (1) the clinical response at the TOCvisit; those patients rated as resolved/cured by the physicians based ona 4-point scale (0=resolved/cured, 1=improved, 2=not changed,3=worsened); and (2) the microbiological response, success or failure,at the TOC visit for patients with positive pre-therapy cultures.Secondary efficacy variables were (1) the time to cessation of otorrheaas recorded in the patient diary; and as assessed by the physician's ateach visit (2) the clinical response based on a 4-point scale(0=resolved/cured, 1=improved, 2=not changed, 3=worsened); (3) thegranulation tissue based on a 4-point scale (0=none, 1=mild, 2=moderateand 3=severe); (4) the presence or absence of otorrhea; (5) the otorrheavolume based on a 4-point scale (0=absent, 1=scant, 2=moderate and3=severe); and the color/type of otorrhea based on a 5-point scale(0=absent, 1=serous, 2=mucoid, 3=purulent, 4=sanguineous).

Safety:

The safety evaluation was conducted on all patients who were randomizedinto the study and received at least one dose of study drug. The safetyanalysis was based on the following; extent of exposure to study drug;adverse events; and audiometry examination.

Statistical Methods:

The statistical objective was to demonstrate the non-inferiority ofCIPRODEX relative to FLOXIN in clinical and microbiological response atthe TOC visit. Two-sided 95% confidence intervals for the differencebetween proportions between the two treatment groups were constructed.However, due to the lack of zero within the confidence limits,non-inferiority was demonstrated, and analyses allowed for a claim ofsuperiority. Therefore, differences between the two treatments forclinical and microbiological response were evaluated using theChi-square test of independence. For analyses of the secondaryvariables, the number and proportion of patients per response in eachtreatment group was presented and differences were assessed usingLSMEANS (Mixed Model Analysis of Variance) or the Chi-square test ofindependence as appropriate. The log-rank test (Kaplan-Meier survivalanalysis was conducted to compare median time to cessation of otorrheabetween the two treatments.

Summary Conclusions

-   -   CIPRODEX Otic Suspension is superior to FLOXIN Otic Solution in        clinical and microbiological response at the test of cure (TOC)        visit; and    -   CIPRODEX Otic Suspension is effective and safe for the treatment        of pediatric patients with acute otitis media and otorrhea with        tympanosotomy tubes (AOMT).

These data demonstrate the superior effectiveness of CIPRODEX, anantibiotic-steroid combination drug, for the treatment of AOMT as shownin comparative analyses to a marketed product approved for the sameindication.

This study evaluated the efficacy and safety of CIPRODEX, anantibiotic-steroid combination product (ciprofloxacin 0.3%/dexamethasone0.1%) compared to FLOXIN, which contains antibiotic alone (ofloxacin0.3%). The study duration was approximately three weeks long with fourscheduled visits. Conditions between the treatment groups were identicalexcept for the study drugs and the respective dosing regimens. Bothdrugs were topically administered BID, however, the FLOXIN groupreceived 5 drops per dose for 10 days (per the package insert) and theCIPRODEX group, 4 drops per dose for 7 days. Outcome differences betweenthe two groups are therefore attributed to the differences in treatment.

Efficacy Results:

A total of 599 patients were evaluable for the ITT analyses, 424 for theMITT, 460 for the PP and 357 for the MPP analyses. Of the ITT data set,62% were male, 81% were Caucasian, 41% enrolled the right ear, 36%enrolled the left ear, and 23% enrolled both ears. The mean age was 2.45years and the mean duration of the current episode of AOMT was 4.49 daysin the right ear and 4.71 days in the left ear. In primary analyses, atthe TOC visit, CIPRODEX was superior to FLOXIN for clinical cures forall data sets (p≦0.0027) and for microbiological eradication for MITTand MPP data sets (p≦0.0061). Additionally, for all data sets, CIPRODEXwas superior to FLOXIN for treatment failure rate (p≦0.0189). Inanalyses of the secondary efficacy variables, CIPRODEX was superior toFLOXIN for time to cessation of otorrhea for all data sets (p≦0.018).Clinically, this translates to the cessation of otorrhea in 20 to 33%less time for the CIPRODEX treated patients in comparison to the FLOXINtreated patients (median time of 4 days for CIPRODEX versus 5-6 days forFLOXIN). For the remaining secondary efficacy variables, improvement inclinical response, absence of otorrhea, reduction in otorrhea volume andabsence of otorrhea color, CIPRODEX was superior to FLOXIN at everystudy visit after baseline (p≦0.0023, p≦0.0012, p≦0.0003, and p≦0.0003,respectively). Moreover, at study visits Day 11 and Day 18, CIPRODEX wassuperior to FLOXIN for reduction in granulation tissue (p=0.0086 andp=0.0383, respectively). These outcomes demonstrate that CIPRODEX is notonly a more effective treatment for AOMT in comparison to FLOXIN, butalso results in a more rapid response to treatment and resolution of theclinical signs and symptoms of AOMT relative to FLOXIN. CIPRODEX iseffective in treating acute otitis media with otorrhea in tympanostomy(AOMT) patients and results in 90% patients with clinical cure, 92%patients with microbiological success and a 4-day median time tocessation of otorrhea.

Efficacy Conclusions:

1. CIPRODEX is superior to FLOXIN for clinical cures at the TOC visit.

Clinical Cure Rates and 95% Confidence Intervals by Treatment Group (AllData Sets) Treatment CIPRODEX FLOXIN Clinical Cure Clinical Cure No YesNo Yes Data Set N % N % N % N % Delta Lower Upper P-value^(a) ITT 7525.25 222 74.75 117 38.74 185 61.26 13.49 6.10 20.88 0.0004 MITT 4320.67 165 79.33 78 36.11 138 63.89 15.44 6.99 23.88 0.0004 PP 28 12.07204 87.93 50 22.73 170 77.27 10.66 3.71 17.60 0.0027 MPP 18 10.00 16290.00 37 21.76 133 78.24 11.76 4.17 19.36 0.0025 ^(a)Chi-square test ofindependence (Fisher's exact test when N < 5).2. CIPRODEX is superior to FLOXIN for microbiological eradication at theTOC visit.

Microbiological Eradication Rates and 95% Confidence Intervals byTreatment Group (All Data Sets) Treatment CIPRODEX FLOXINMicrobiological Microbiological Eradication Eradication Failure SuccessFailure Success Data Set N % N % N % N % Delta Lower Upper P-value^(a)ITT 128 43.10 169 56.90 154 50.99 148 49.01 7.90 −0.07 15.87 0.0529 MITT41 19.71 167 80.29 72 33.33 144 66.67 13.62 5.33 21.91 0.0015 PP 6728.88 165 71.12 81 36.82 139 63.18 7.94 −0.70 16.58 0.0722 MPP 15 8.33165 91.67 31 18.24 139 81.76 9.90 2.83 16.97 0.0061 ^(a)Chi-square testof independence (Fisher's exact test when N < 5).3. CIPRODEX is superior to FLOXIN for treatment failure rate.

Discontinuations Due to Treatment Failure by Treatment Group TreatmentCIPRODEX FLOXIN Treatment Failure Treatment Failure No Yes No Yes DataSet N % N % N % N % P-value^(a) ITT 281 94.61 16 5.39 270 89.40 32 10.600.0189 MITT 199 95.67 9 4.33 192 88.89 24 11.11 0.0091 PP 220 94.83 125.17 188 85.45 32 14.55 0.0008 MPP 172 95.56 8 4.44 146 85.88 24 14.120.0017 ^(a)Chi-square test of independence (Fisher's exact test when N <5).4. CIPRODEX is superior to FLOXIN for improvement in clinical responseat Days 3, 11 and 18.

Clinical Response by Treatment Group (MITT) Treatment CIPRODEX FLOXINVisit Clinical Response N % N % P-value^(a) Day 3 Missing 1 0 0 0 <.0001Cured 64 30.92 38 17.59 Improved 130 62.80 134 62.04 Unchanged 9 4.35 3516.20 Worse 4 1.93 9 4.17 Day 11 Missing 1 0 0 0 <.0001 Cured 174 84.06136 62.96 Improved 25 12.08 58 26.85 Unchanged 4 1.93 12 5.56 Worse 41.93 10 4.63 Day 18 Missing 1 0 0 0 0.0023 Cured 174 84.06 153 70.83Improved 20 9.66 38 17.59 Unchanged 6 2.90 12 5.56 Worse 7 3.38 13 6.02^(a)Treatment difference from LSMEANS (Mixed Model Analysis ofVariance).5. CIPRODEX is superior to FLOXIN for time to cessation of otorrhea.

Time to Cessation of Otorrhea by Treatment Group (MITT) TreatmentCIPRODEX FLOXIN P-value^(a) Mean 6.02 7.10 0.0204 Median 4.00 5.00 Std4.87 4.68 N 208 216 Min 2 2 Max 21 21 ^(a)Log-rank test (Kaplan-Meiersurvival analysis).6. CIPRODEX is superior to FLOXIN for absence of otorrhea at Days 3, 11and 18.

Presence/Absence of Otorrhea by Treatment Group (MITT) TreatmentCIPRODEX FLOXIN Visit Otorrhea N % N % P-value^(a) Day 1 Present 208100.00 216 100.00 Day 3 Absent 67 32.21 40 18.52 0.0012 Present 14167.79 176 81.48 Day 11 Absent 176 84.62 137 63.43 <.0001 Present 3215.38 79 36.57 Day 18 Missing 1 0 0 0 0.0004 Absent 176 85.02 153 70.83Present 31 14.98 63 29.17 ^(a)Chi-square test of independence (Fisher'sexact test when N < 5).7. CIPRODEX is superior to FLOXIN for reduction in granulation tissue atDays 11 and 18.

Granulation Tissue by Treatment Group (MITT) Treatment CIPRODEX FLOXINVisit Granulation Tissue N % N % P-value^(a) Day 1 Absent 159 76.44 17581.02 0.3449 Mild 30 14.42 21 9.72 Moderate 15 7.21 16 7.41 Severe 41.92 4 1.85 Day 3 Missing 1 0 0 0 0.3285 Absent 177 85.51 182 84.26 Mild24 11.59 22 10.19 Moderate 6 2.90 10 4.63 Severe 0 0.00 2 0.93 Day 11Missing 1 0 0 0 0.0086 Absent 198 95.65 186 86.11 Mild 8 3.86 22 10.19Moderate 1 0.48 8 3.70 Day 18 Missing 1 0 0 0 0.0383 Absent 203 98.07192 88.89 Mild 3 1.45 21 9.72 Moderate 1 0.48 3 1.39 ^(a)Treatmentdifference from LSMEANS (Mixed Model Analysis of Variance).8. CIPRODEX is superior to FLOXIN for reduction in otorrhea volume atDays 3, 11 and 18.

Volume by Treatment Group (MITT) Treatment CIPRODEX FLOXIN Visit VolumeN % N % P-value^(a) Day 1 Scant 17 8.17 14 6.48 0.3195 Moderate 10450.00 99 45.83 Copious 87 41.83 103 47.69 Day 3 Missing 1 0 0 0 <.0001Absent 66 31.88 39 18.06 Scant 98 47.34 84 38.89 Moderate 34 16.43 7735.65 Copious 9 4.35 16 7.41 Day 11 Missing 1 0 0 0 <.0001 Absent 17584.54 136 62.96 Scant 19 9.18 42 19.44 Moderate 7 3.38 26 12.04 Copious6 2.90 12 5.56 Day 18 Missing 2 0 0 0 0.0003 Absent 175 84.95 153 70.83Scant 14 6.80 21 9.72 Moderate 8 3.88 27 12.50 Copious 9 4.37 15 6.94^(a)Treatment difference from LSMEANS (Mixed Model Analysis ofVariance).9. CIPRODEX is superior to FLOXIN for absence of otorrhea color and lesspurulent otorrhea at Day 3, and absence of otorrhea color and lessmucoid otorrhea at Days 11 and 18.

Color/Type by Treatment Group (MITT) Treatment CIPRODEX FLOXIN VisitColor/Type N % N % P-value ^(a) Day 1 Absent 0 0 0 0 ^(b) Serous 2160.00 14 40.00 0.2301 Mucoid 100 54.64 83 45.36 0.1417 Purulent 14946.71 170 53.29 0.0607 Sanguineous 14 48.28 15 51.72 0.8335 Day 3 Absent67 63.21 39 36.79 0.0003 Serous 55 48.67 58 51.33 0.8593 Mucoid 63 43.7581 56.25 0.2244 Purulent 36 38.71 57 61.29 0.0461 Sanguineous 1 14.29 685.71 0.1244 Day 11 Absent 176 56.23 137 43.77 0.0000 Serous 12 34.29 2365.71 0.0770 Mucoid 7 15.91 37 84.09 0.0000 Purulent 14 40.00 21 60.000.2879 Sanguineous 0 0.00 3 100.00 0.2488 Day 18 Absent 176 53.50 15346.50 0.0002 Serous 8 44.44 10 55.56 0.7183 Mucoid 7 18.42 31 81.580.0001 Purulent 18 41.86 25 58.14 0.3510 Sanguineous 0 0.00 2 100.000.4992 ^(a) Chi-square test of independence (Fisher's exact test when N< 5). ^(b) Could not be calculated.Safety Results:

The safety of CIPRODEX and FLOXIN was evaluated in 599 pediatricpatients with acute otitis media with tympanostomy tubes. No seriousadverse events related to therapy were reported during this study.Seventy-eight patients (CIPRODEX: 32; FLOXIN: 46) were discontinued fromthe study due to adverse events, of which 76 were due totreatment-unrelated events. Adverse events in the overall safetypopulation were all nonserious with the exception of three reports(abdominal pain, pneumonia, cellulitis), were generally mild tomoderate, usually resolved with or without treatment, and generally didnot interrupt patient continuation in the study. Similar types of oticand nonotic adverse events were noted in the infant and toddlerpopulation and the children population for CIPRODEX and FLOXIN. Therewere no trends observed in the analysis of adverse events according toage category either within or between CIPRODEX and FLOXIN treatmentgroups. Only three patients in the adolescent population were enrolled,and none of the adolescents reported adverse events.

Audiometry testing was performed to further assess the safety ofCIPRODEX in the pediatric population. No clinically relevant orstatistically significant (p=0.3863) difference in mean change of speechreception threshold (SRT) from baseline was observed between CIPRODEXand FLOXIN, and no clinically relevant decrease in hearing from baselinewas observed with CIPRODEX or FLOXIN, based upon an assessment of boneand air conduction audiometry parameters.

CIPRODEX administered twice daily in the affected ear(s) is safe andwell tolerated in pediatric patients with acute otitis media withtympanostomy tubes, based upon a review of adverse events and anassessment of audiometry parameters.

Safety Conclusions:

1. CIPRODEX administered twice daily in the affected ear(s) is safe andwell tolerated in pediatric patients with acute otitis media withtympanostomy tubes, based upon a review of adverse events and anassessment of audiometry parameters.

2. Adverse events in the overall safety population were all nonseriouswith the exception of three reports (abdominal pain, pneumonia,cellulitis), were generally mild to moderate, usually resolved with orwithout treatment, and generally did not interrupt patient continuationin the study.3. No clinically relevant or statistically significant difference inmean change of speech recognition threshold (SRT) from baseline wasobserved between CIPRODEX and FLOXIN.4. No clinically relevant decrease in hearing from baseline was observedwith CIPRODEX or FLOXIN, based upon an assessment of bone and airconduction audiometry parameters.

The invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

What is claimed is:
 1. A method of treating a middle ear infection in ahuman patient comprising the steps of: (a) diagnosing the patient ashaving otitis media and an open tympanic membrane in at least one ear;and (b) topically applying into the ear canal of the patient's ear anaqueous suspension composition containing a combination of ciprofloxacinand dexamethasone, wherein the composition comprises a) 0.01-0.5% (wt.)dexamethasone, wherein the dexamethasone has an average particle size ona mean volume basis of less than 10 μM; b) 0.1-0.4% (wt.) ciprofloxacin;c) 0.1-0.9% (wt.) tonicity agent; d) 0.01-0.2% (wt.) of a nonionicsurfactant; e) a buffer; and wherein the composition has a pH from about3-5.
 2. The method of claim 1 wherein the dexamethasone is dexamethasonealcohol and the ciprofloxacin is ciprofloxacin hydrochloride,monohydrate.
 3. The method of claim 1 wherein the aqueous suspensioncomposition contains 0.1% (wt.) dexamethasone and 0.3% (wt.)ciprofloxacin.
 4. The method of claim 3 wherein three or four drops ofthe aqueous suspension composition are administered to the patient's eartwice a day, wherein each drop is 30-35 μL.
 5. The method of claim 1wherein the aqueous suspension composition consists essentially of a)0.1% (wt.) dexamethasone alcohol; b) 0.35% (wt.) ciprofloxacinhydrochloride, monohydrate; c) NaCl in an amount sufficient to cause thecomposition to have an osmolality of about 250-350 mOsm; d) 0.2% (wt.)hydroxyethyl cellulose; e) 0.05% (wt.) tyloxapol; f) a buffer comprisingsodium acetate and acetic acid; g) 0.01% (wt.) benzalkonium chloride; h)0.01% (wt.) edetate disodium; i) 0.6% (wt.) boric acid; and wherein thecomposition has a pH of about 4.5.
 6. The method of claim 1 wherein themethod further comprises the step of pumping the tragus to force theaqueous suspension composition through the open tympanic membrane andinto the middle ear.
 7. The method of claim 1 wherein the dexamethasonehas an average particle size on a mean volume basis of less than 3 μm.8. The method of claim 1 wherein the otitis media is acute otitis media.9. The method of claim 1 wherein the otitis media is chronic suppurativeotitis media.
 10. The method of claim 1 wherein the aqueous suspensioncomposition containing a combination of ciprofloxacin and dexamethasoneis packaged with directions for use that indicate the composition may beused to treat otitis media in patients with an open tympanic membrane.